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Polθ 参与替代性DNA修复

容易出错的“非同源末端连接”(NHEJ) DNA修复通道在当无错误的同源重组通道受到影响时用作一个替代性修复通道,或是某些细胞环境中(如在免疫系统中)的首选修复通道。在断裂的末端通过 “microhomology”接上之后,NHEJ取决于DNA合成,但其中所涉及的聚合酶的身份此前却不清楚。

现在,来自Agnel Sfeir和Alan D’Andrea两个实验室的两项研究表明,哺乳动物的POLQ 基因(编码容易出错的聚合酶Polθ)参与了这一过程。

Sfeir及同事发现,在端粒脱保护时,需要Polθ来防止在端粒上发生替代性末端连接和在非端粒序列上发生染色体翻译。

D’Andrea 及同事关注Polθ 在癌细胞中的作用,发现在“同源重组不足”背景下,Polθ 的缺失导致“合成致死”(synthetic lethality),从而提出了一个可能的治疗方法。

原文链接:

Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination

The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions1, 2, 3. Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Polθ; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Polθ has a synergistic effect on cell survival in the absence ofBRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.(doi:10.1038/nature14157)

Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair

Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair1. Loss of HR accounts for the genomic instability of EOCs and for their cellular hyper-dependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms2, 3, 4, 5. Previous studies have implicated the DNA polymerase θ (Polθ also known as POLQ, encoded by POLQ)6 in a pathway required for the repair of DNA double-strand breaks7, 8, 9, referred to as the error-prone microhomology-mediated end-joining (MMEJ) pathway10, 11, 12, 13. Whether Polθ interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Polθ expression in EOCs. Knockdown of Polθ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Polθ in HR-deficient EOCs enhances cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, Polθ contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Polθ-mediated repair in EOCs, and identify Polθas a novel druggable target for cancer therapy.